KR101741367B1 - Composition for protecting allergic response comprising the extract of Penthorun chinense Pursh - Google Patents
Composition for protecting allergic response comprising the extract of Penthorun chinense Pursh Download PDFInfo
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- KR101741367B1 KR101741367B1 KR1020160121708A KR20160121708A KR101741367B1 KR 101741367 B1 KR101741367 B1 KR 101741367B1 KR 1020160121708 A KR1020160121708 A KR 1020160121708A KR 20160121708 A KR20160121708 A KR 20160121708A KR 101741367 B1 KR101741367 B1 KR 101741367B1
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- octopus
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- allergic
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- A23V2200/304—Foods, ingredients or supplements having a functional effect on health having a modulation effect on allergy and risk of allergy
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Abstract
본 발명은 알레르기 억제용 조성물에 관한 것으로, 더욱 자세하게는 낙지다리(Penthorum chinense Pursh) 추출물을 유효성분으로 함유하는 알레르기 억제용 약제학적 조성물 및 알레르기 반응 억제 및 개선용 건강기능식품에 관한 것이다. 본 발명의 낙지다리 추출물은 비만세포 억제 효과 및 알레르기 유발 동물모델에서의 알레르기 억제 효과가 뛰어나므로, 이를 유효성분으로 포함하는 조성물은 알레르기 질환의 예방 또는 치료에 적합한 의약품 뿐만 아니라 알레르기 증상을 개선시키기 위한 건강기능식품 등으로 활용할 수 있다.The present invention relates to a composition for inhibiting allergy, and more particularly, to a pharmaceutical composition for inhibiting allergy comprising an extract of Octopus chinense Pursh as an active ingredient and a health functional food for suppressing and improving an allergic reaction. Since the octopus legs extract of the present invention is excellent in an inhibitory effect on mast cells and an allergen suppressing effect in an allergen-induced animal model, the composition containing the extract as an active ingredient is useful as a medicament suitable for prevention or treatment of allergic diseases, Health functional foods, etc.
Description
본 발명은 알레르기 억제용 조성물에 관한 것으로, 자세하게는 낙지다리 추출물을 유효성분으로 함유하는 알레르기 반응 억제용 약제학적 조성물 및 알레르기 반응 억제 및 개선용 건강기능식품에 관한 것이다.TECHNICAL FIELD The present invention relates to a composition for inhibiting allergy, and more particularly, to a pharmaceutical composition for inhibiting an allergic reaction containing octopus leg extract as an active ingredient and a health functional food for suppressing and improving an allergic reaction.
현대 사회는 기후 변화에 따른 생태계 변화, 대기오염, 황사, 실내주거환경, 서구화된 식습관 등에 의하여 천식, 알레르기 비염, 아토피, 만성 폐쇄성폐질환 등 알레르기 질환이 증가 추세를 보이고 있다(선행문헌 1).In modern society, allergic diseases such as asthma, allergic rhinitis, atopy and chronic obstructive pulmonary disease are increasing due to ecosystem change due to climate change, air pollution, dust, indoor living environment and westernized eating habits (Prior Art 1).
질병관리본부가 실시한「천식 및 알레르기질환 조사」 결과에 따르면, 최근 15년간(`95년 - `10년) 알레르기 비염은 어린이 1.3배, 청소년은 1.4배 증가했고, 알레르기결막염은 어린이 1.9배, 청소년 1.9배 증가했다고 발표했다. 이와 같이 알레르기 발병률은 어린아이로부터 성인까지 계속해서 증가하는 추세이다(선행문헌 10). 특히, 알레르기 질환의 대상이 어린아이까지 확대되면서 사회적 이슈가 되고 있으며 다양한 알레르기 질환 치료제들이 개발되고 있는 상황이다. 현재 알레르기 치료제로는 알레르기를 일으키는 알레르겐(allergen)으로부터 보호하는 물리적 방법, 항히스타민제, 류코트리엔 수용체 길항제 등이 있는데, 이 중 가장 널리 쓰이는 항히스타민제는 알레르기 반응 시, 체내에 과다하게 분비되는 히스타민을 억제함으로 알레르기 반응을 감소시키는 효과를 가지고 있지만, 과량으로 사용할 경우 중추신경계 억제 및 녹내장, 전립선 비대 등 다양한 부작용을 동반하고 있다(선행문헌 11). 이와같이 현재 시판 되고 있는 약물 중 알레르기를 근본적으로 치료할 수 있는 치료법은 미비한 상태이다. 따라서 알레르기 질환을 치료할 근본적인 연구가 필요하다.According to the results of the "Asthma and Allergy Disease Survey" conducted by the Disease Control Center, allergic rhinitis has increased 1.3 times in children and 1.4 times in adults over the past 15 years (95 years to 10 years). Allergic conjunctivitis, 1.9 times higher than the previous year. Thus, the incidence of allergies continues to increase from infants to adults (Prior Art 10). Especially, as the subject of allergic diseases is expanding to children, it is becoming a social issue, and various allergic disease drugs are being developed. Currently, anti-allergic agents include allergens, physical methods to protect them from allergens, antihistamines, leukotriene receptor antagonists, etc. Among them, the most widely used antihistamines are those that inhibit excessive secretion of histamine in the body during allergic reactions Although it has the effect of reducing the allergic reaction, when it is used in excess, various side effects such as central nervous system depression, glaucoma, and enlargement of the prostate are accompanied (Prior Art 11). Thus, there is no treatment available to fundamentally treat allergies among currently marketed drugs. Therefore, fundamental research to treat allergic diseases is needed.
외부 알레르겐(allergen)이 우리 몸속으로 침입하면, B 림프구는 침입한 알레르겐을 인식하고, 형질세포로 분화한다. 이때 분화된 형질세포는 항원을 특이적으로 인식하는 IgE (Immunoglobulin E)를 분비하게 된다. 이러한 조건에 의하여 항원 특이 IgE 항체가 비정상적으로 증가하게 되며 증가한 IgE는 비만세포 표면의 IgE 고 친화성 수용체(FcεRI, high-affinity receptor for IgE)에 결합하여 외부로부터 알레르겐(allergen)이 다시 들어오면 항원-항체 반응이 진행되면서 비만세포를 활성화시킨다(선행문헌 2).When an external allergen enters our body, B lymphocytes recognize the invading allergen and differentiate into plasma cells. At this time, the differentiated plasma cells secrete IgE (Immunoglobulin E) that specifically recognizes the antigen. These conditions increase the antigen-specific IgE antibody abnormally and the increased IgE binds to the IgE high affinity receptor (FcεRI, high-affinity receptor for IgE) on the surface of the mast cell, and when the allergen comes back from the outside, - Activates mast cells as the antibody reaction progresses (Prior Art 2).
비만세포는 세포 내에 과립들을 가지고 있는데, 비만세포가 활성화되면 세포 내의 과립에 저장되어 있던 히스타민, 헤파린 및 단백분해효소 등이 세포 밖으로 분비되고 류코트리엔, 프로스타글란딘 등의 화학매개체들을 만들어 낸다. 이러한 화학매개체들은 짧은 시간 내에 혈관을 확장시켜 투과성을 증가시키고 우리 몸의 평활근 수축 및 분비선의 기능을 증가시켜 알레르기 증상을 유도한다(선행문헌 3).Mast cells have granules in the cells. When mast cells are activated, histamine, heparin, and proteolytic enzymes stored in the granules in the cells are secreted out of the cells and produced chemical mediators such as leukotrienes and prostaglandins. These chemical agents expand the blood vessels in a short time to increase the permeability and increase the function of the smooth muscle contraction and gland of the body, leading to allergic symptoms (Preceding document 3).
비만세포 표면에 존재하는 FcεRI는 α, β, γ-서브유닛으로 구성되어있다(선행문헌 4). 이 중 β, γ-서브유닛은 세포 내 신호전달에 관여한다. 알레르겐이 IgE와 교차결합하면 β-서브유닛에 결합되어있던 Src-키나아제에 의해 수용체가 인산화 되면서 세포 내 신호전달이 시작된다. 또한 β, γ-서브유닛은 수용체에 결합되어있던 Lyn 키나아제에 의해 ITAM (Immunoreceptor tyrosine-based activation mitif)이 인산화 된다(선행문헌 5). 인산화된 ITAM은 세포 활성화에 중요한 역할을 하는 Syk 키나아제의 결합부위를 제공하여 Syk 키나아제를 활성화 시키고 그 후 아래의 하위 신호전달물질의 활성화를 유도한다(선행문헌 6).FcεRI present on the surface of mast cells consists of α, β, γ-subunits (Prior Art 4). Among these, β, γ-subunits are involved in intracellular signal transduction. When allergens cross-link with IgE, the receptor is phosphorylated by Src-kinase bound to the? -Subunit and intracellular signaling begins. The β, γ-subunit is phosphorylated by the Lyn kinase that is bound to the receptor (Immunoreceptor tyrosine-based activation mitif) (Prior Art 5). Phosphorylated ITAM provides a binding site for Syk kinase that plays an important role in cell activation, activating Syk kinase and then inducing activation of the lower signaling substance (Prior Art 6).
항원에 의한 비만세포 활성화 과정 초기에 가장 중요한 신호전달 단백질인 Syk가 활성화되면서 하위 신호전달 LAT (Linker for activation of T cells), PL(phospholipase)-Cγ, PKC (protein kinase C) 등 다양한 신호전달 물질이 활성화되고, 결과적으로 비만세포가 활성화되면서 히스타민, 프로스타글라딘, 루코트리엔 및 과민증 인자 등을 분비하여 면역체계를 활성화시켜 염증 및 알레르기를 발생시킨다(선행문헌 7). 이와 같이 세포내 신호전달 기전에 대한 연구는 알레르기 질환 연구에서 중요한 부분을 차지한다.In the early stage of activation of mast cell by antigen, Syk, which is the most important signaling protein, is activated and a variety of signaling substances such as LAT (Linker for activation of T cells), PL (phospholipase) -Cγ and PKC (protein kinase C) , And as a result, mast cells are activated and secrete histamine, prostaglandin, rucotriene, and hypersensitivity factors, thereby activating the immune system to cause inflammation and allergy (Prior Art 7). Thus, studies on intracellular signal transduction mechanisms are an important part of allergy disease research.
한편, 낙지다리(Penthorum chinense Pursh)는 돌나물과(Crassulaceae)의 다년생 초본으로 근경이나 종자로 번식한다. 전국적으로 분포하며 강가나 풀밭의 습기가 많은 곳에 분포한다. 높이는 60 - 90cm이며 잎은 어긋나고 잎자루가 거의 없다. 초여름에 누르스름한 작은 꽃이 이삭 모양으로 줄기 끝에 피고 열매는 삭과(朔果)로 익으면 갈라진다. 어린싹은 식용한다. 들의 습지에서 자라는데 한국, 중국, 일본 등지에 분포한다.On the other hand, the octopus leg (Penthorum chinense Pursh ) is a perennial herb of Crassulaceae and reproduces as rhizomes or seeds. It is distributed throughout the country and is distributed in wet areas of rivers and grasses. The height is 60 - 90cm, the leaves are staggered and there are few petiole. A small flower in early summer is in the shape of a spike and blooms at the end of the stem. The fruit is split when it is ripe in an eggplant (朔 果). Young shoots are edible. It grows in the wetlands of Korea, China, and Japan.
이러한 낙지다리 추출물은 간과 신경세포 보호의 효과가 있는 것으로 보고되어 있다(선행문헌 8). 하지만 알레르기 질환에 대한 낙지다리의 대한 보고는 존재하지 않는다.These octopus legs extracts have been reported to have liver and nerve cell protection (Prior Art 8). However, there is no report of octopus legs for allergic diseases.
이에, 본 발명자들은 천연 식물 추출물의 알레르기 반응 억제 효과를 확인하기 위해 알레르기 반응에 의해 활성화되는 비만세포 억제 효과 및 알레르기 유발 동물모델에서의 알레르기 억제 실험을 수행한 결과, 낙지다리 추출물의 비만세포 억제 효과 및 알레르기 유발 동물모델에서 알레르기 억제 효과가 우수함을 확인함으로써 본 발명을 완성하였다.In order to confirm the inhibitory effect of the natural plant extract on the allergic reaction, the present inventors conducted an experiment to inhibit allergic mast cell activation and allergen inhibition in allergen-induced animal models. As a result, And an allergen-inhibiting animal model, the present invention has been completed.
본 발명의 목적은 천연 식물 추출물을 유효성분으로 함유하는 알레르기 억제용 약제학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for inhibiting allergy comprising a natural plant extract as an active ingredient.
본 발명의 또 다른 목적은 천연 식물 추출물을 유효성분으로 함유하는 알레르기 억제 또는 개선용 건강기능식품을 제공하는 것이다.Yet another object of the present invention is to provide a health functional food for suppressing or improving allergies comprising a natural plant extract as an active ingredient.
상기 목적을 달성하기 위해, 본 발명은 낙지다리 추출물을 유효성분으로 함유하는 알레르기 억제용 약제학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for inhibiting allergy comprising octopus leg extract as an active ingredient.
본 발명은 또한 낙지다리 추출물을 유효성분으로 함유하는 알레르기 억제 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for suppressing or improving allergies comprising octopus leg extract as an active ingredient.
본 발명의 낙지다리 추출물은 항원 자극에 의한 비만세포의 탈과립, 사이토카인 분비 및 동물모델에서 알레르기 반응을 세포내 Syk/LAT 신호전달경로를 억제함으로써 알레르기 반응 억제 효과가 뛰어나다.The octopus legs extract of the present invention is excellent in suppressing the allergic reaction by suppressing intracellular Syk / LAT signaling pathway by degranulation of mast cells, secretion of cytokines and allergic reaction in an animal model by antigen stimulation.
도 1은 낙지다리 추출물의 처리 농도별 비만세포 탈과립 억제 효과를 확인한 β-헥소스아미니다이제 분비 억제 정도를 %로 나타낸 그래프이다.
도 2는 낙지다리 추출물의 처리 농도별 비만세포 탈과립 억제 효과 가역성을 확인한 β-헥소스아미니다이제 분비 억제 정도를 %로 나타낸 그래프이다.
도 3은 낙지다리 추출물의 처리 농도별 비만세포에서의 염증성 사이토카인 분비 억제 효과를 TNF-α 및 IL-4의 mRNA 발현 정도로 확인한 RT-PCR 결과이다. Ag로 표시한 그래프가 항원을 처리한 것을 나타낸다.
도 4는 낙지다리 추출물의 처리 농도별 비만세포에서의 칼슘 농도 증가에 따른 탈과립 억제 효과를 확인한 β-헥소스아미니다이제 분비 억제 정도를 %로 나타낸 그래프이다. 도면에서, Ion은 이오노마이신, Tg는 탭시가긴이다.
도 5는 낙지다리 추출물의 처리 농도별 비만세포(상단은 RBL-2H3 세포, 하단은 BMMC 세포)에서의 Syk 키나아제 및 LAT 키나아제 인산화 억제 효과를 확인한 면역분석 결과이다.
도 6은 낙지다리 추출물의 처리 농도별 국소피부자극 알레르기 반응 억제 효과를 확인한 에반스블루 흡광도 측정 결과이다. 도면에서 CZ는 대조군인 세티리진이다.
도 1 내지 도 6에서 공통적으로, PCE는 낙지다리 추출물이다.FIG. 1 is a graph showing percent inhibition of β-hexosaminidase secretion by confirming the inhibitory effect on mast cell degranulation by the treatment concentration of octopus leg extract.
FIG. 2 is a graph showing percent inhibition of β-hexosaminidase secretion by confirming the reversibility of mast cell degranulation inhibitory effect according to the treatment concentration of octopus legum extract.
FIG. 3 shows RT-PCR results of inhibiting the secretion of inflammatory cytokines in mast cells according to the treatment concentration of Octopus legum extract as the degree of mRNA expression of TNF-α and IL-4. The graph labeled Ag shows that the antigen has been treated.
FIG. 4 is a graph showing percent inhibition of β-hexosaminidase secretion by confirming the inhibitory effect of degunase inhibition upon increasing calcium concentration in mast cells according to the treatment concentration of octopus leg extract. In the figure, Ion is ionomycin and Tg is tapshield.
FIG. 5 shows the immunoassay results of inhibiting Syk kinase and LAT kinase phosphorylation in mast cells (RBL-2H3 cells on the upper side and BMMC cells on the lower side) according to treatment concentration of octopus leg extract.
FIG. 6 shows the results of measurement of Evans blue absorbance by confirming the effect of inhibiting local skin irritation allergic reaction by treatment concentration of octopus leg extract. In the figure, CZ is a control group, cetirizine.
1 to 6, PCE is an octopus leg extract.
본 발명은 낙지다리 추출물을 유효성분으로 함유하는 알레르기 질환 예방, 개선 또는 치료용 약제학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing, ameliorating or treating an allergic disease containing Octopus legum extract as an active ingredient.
본 발명에서 용어, `예방`이란 조성물의 투여에 의해 알레르기 반응을 억제시키거나 알레르기 반응에 의한 질환의 발병을 지연시키는 모든 행위를 의미한다.The term ' prophylactic ' in the present invention means all actions which inhibit the allergic reaction by administration of the composition or delay the onset of the disease caused by the allergic reaction.
본 발명에서 용어, `치료`란 조성물의 투여에 의해 알레르기 반응에 의한 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다.The term " treatment " in the present invention means all the actions of alleviating or alleviating symptoms of an allergic disease caused by the administration of the composition.
본 발명의 `낙지다리(Penthorum chinense Pursh)`는 돌나물과(Crassulaceae)의 다년생 초본으로 근경이나 종자로 번식한다. 전국적으로 분포하며 강가나 풀밭의 습기가 많은 곳에 분포한다. 높이는 60 - 90cm이며 잎은 어긋나고 잎자루가 거의 없다. 초여름에 누르스름한 작은 꽃이 이삭 모양으로 줄기 끝에 피고 열매는 삭과(朔果)로 익으면 갈라진다. 어린싹은 식용한다. 들의 습지에서 자라는데 한국, 중국, 일본 등지에 분포한다.The " Penthorum " chinense Pursh ) is a perennial herb of Crassulaceae that reproduces as rhizomes or seeds. It is distributed throughout the country and is distributed in wet areas of rivers and grasses. The height is 60 - 90cm, the leaves are staggered and there are few petiole. A small flower in early summer is in the shape of a spike and blooms at the end of the stem. The fruit is split when it is ripe in an eggplant (朔 果). Young shoots are edible. It grows in the wetlands of Korea, China, and Japan.
낙지다리 추출물은 간과 신경세포의 보호 효과가 있는 것으로 보고되어 있다(선행문헌 8). 하지만 알레르기 질환에 대한 낙지다리의 대한 보고는 존재하지 않는다. 본 발명에서는 낙지다리 추출물의 비만세포 억제 효과 및 알레르기 유발 동물모델에서 알레르기 억제 효과 등을 규명하기 위해 수행하였다.Octopus legs extracts have been reported to have protective effects on liver and nerve cells (Prior Art 8). However, there is no report of octopus legs for allergic diseases. In the present invention, the effect of the extract of octopus legs on mast cell inhibition and the allergic inhibitory effect in allergy-induced animal models were investigated.
본 발명에 따른 낙지다리 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 추출 및 분리하여 수득한 것을 사용할 수 있으며, 본 발명에서 낙지다리 추출물은 낙지다리의 전초를 사용하여 적절한 용매를 이용하여 추출한 것이다.The octopus legs extract according to the present invention can be obtained by extracting and isolating using extracting and separating methods known in the art. In the present invention, the octopus legs extract can be obtained by using a suitable solvent Respectively.
본 발명의 낙지다리 추출물은 다양한 용매를 사용하여 추출할 수 있으며, 바람직하게는 메탄올, 에탄올, 프로탄올, 이소프로판올, 부탄올 등을 포함하는 탄소수 1 내지 4의 저급 알코올, 에틸아세테이트, 아세톤, 에테르, 벤젠, 클로로포름,메틸렌클로라이드, 헥산, 시클로헥산 및 물로 이루어진 군으로부터 선택된 1종 이상의 용매로 추출한 것이며, 가장 바람직하게는 메탄올로 추출한 것이다.The octopus legs extract of the present invention can be extracted using various solvents and is preferably selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, acetone, , Chloroform, methylene chloride, hexane, cyclohexane, and water, and most preferably extracted with methanol.
본 발명의 낙지다리 추출물은 당업계에 공지된 다양한 추출방법에 의해 추출할 수 있으며, 바람직하게는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법 및 용출법으로 구성된 군으로부터 선택된 방법으로 추출하며, 가장 바람직하게는 초음파추출법으로 추출한 것이다.The octopus legs extract of the present invention can be extracted by various extraction methods known in the art and is preferably selected from the group consisting of a hot water extraction method, a cold extraction extraction method, a reflux cooling extraction method, a solvent extraction method, a steam distillation method, an ultrasonic extraction method, And the most preferred method is extraction by an ultrasonic extraction method.
본 발명의 일실시예에 따른 낙지다리 추출물을 제조하는 방법을 조금 더 구체적으로 살펴보면 다음과 같다.The method for preparing octopus legs according to an embodiment of the present invention will be described in more detail as follows.
먼저, 낙지다리 전초에 메탄올 용매를 가하여 초음파 추출기를 이용하여 추출하는 단계; 및 상기 추출 여액을 여과한 후 농축시키는 단계를 거쳐 제조될 수 있다.First, a methanol solvent is added to octopus legs outpost and extracted with an ultrasonic wave extractor; And filtering the extracted filtrate and concentrating the filtrate.
본 발명에 있어서, 낙지다리 추출물은 조성물에 10 내지 1000 mg/㎕의 농도로 포함될 수 있으며, 약제학적 조성물을 인체에 투여하는 경우 10 내지 1000 mg/kg 농도로 투여되는 것이 바람직하며, 100 내지 700 mg/kg 농도로 투여되는 것이 보다 바람직하며, 200 내지 500 mg/kg 농도로 투여되는 것이 가장 바람직하다.In the present invention, octopus leg extract may be contained in the composition at a concentration of 10 to 1000 mg / μl, and when the pharmaceutical composition is administered to a human body, it is preferably administered at a concentration of 10 to 1000 mg / kg, mg / kg, more preferably 200 to 500 mg / kg.
본 발명의 약제학적 조성물로 예방 또는 치료할 수 있는 질환으로는, 알레르기에 의해 유발되는 천식, 알레르기 비염, 아토피, 만성 폐쇄성폐질환으로 이루어진 군으로부터 선택되는 1종 이상이다.The diseases which can be prevented or treated by the pharmaceutical composition of the present invention include at least one selected from asthma, allergic rhinitis, atopy, and chronic obstructive pulmonary disease caused by allergy.
본 발명의 약제학적 조성물은 상기 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The pharmaceutical composition of the present invention can be prepared by using pharmaceutically acceptable and physiologically acceptable adjuvants in addition to the above-mentioned active ingredients. Examples of the adjuvants include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, A lubricant or a flavoring agent can be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.
상기 약제학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation into tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include, but are not limited to, natural sugars such as starch, gelatin, glucose or beta-lactose, natural and synthetic gums such as corn sweeteners, acacia, tracker candles or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.
또한, 본 발명의 낙지다리 추출물을 유효성분으로 포함하는 약제학적 조성물은 경구, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있으며, 바람직하게는 경구 투여가 좋다.In addition, the pharmaceutical composition comprising the octopus leg extract of the present invention as an active ingredient can be administered orally, rectally, intravenously, intraarterally, intraperitoneally, intramuscularly, intrasternally, transdermally, topically, , And preferably oral administration is preferable.
본 발명은 또한, 낙지다리 추출물을 유효성분으로 함유하는 알레르기 반응 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for improving an allergic reaction comprising an octopus leg extract as an active ingredient.
본 발명에서 `건강기능식품`은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term " health functional food " in the present invention refers to a food prepared and processed using raw materials or ingredients having useful functions in accordance with the Health Functional Food Act No. 6727, and the nutrient is controlled Or for the purpose of obtaining a beneficial effect for health use such as physiological action.
본 발명의 건강기능식품은 식품의 형태로서 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류로 이루어진 군으로부터 선택되는 것이 바람직하다.The health functional food of the present invention is selected from the group consisting of beverage, meat, chocolate, food, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, .
본 발명의 건강기능식품은 유효성분인 낙지다리 추출물을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.The health functional food of the present invention may contain various fragrance or natural carbohydrate as an additional ingredient as well as ordinary food composition in addition to octopus leg extract as an effective ingredient.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. The above-described flavors can be advantageously used as natural flavorings (tau martin), stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.).
본 발명의 식품 조성물은 상기 약제학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다.The food composition of the present invention can be formulated in the same manner as the above pharmaceutical composition and used as a functional food or added to various foods.
또한 상기 식품 조성물은 유효성분인 낙지다리 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the octopus legs extract, which is an effective ingredient, the food composition may also contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and intermediates such as cheese and chocolate, Salts of alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
본 발명의 건강기능성식품에 함유된 유효성분인 낙지다리 추출물은 천연물질로부터 유래되어 독성 및 부작용은 거의 없으므로 알레르기 억제 또는 개선의 목적으로 장기간 복용시에도 안심하고 사용할 수 있다.The octopus legs extract, which is an active ingredient contained in the health functional food of the present invention, is derived from a natural substance and has little toxicity and side effects, so that it can be safely used for long-term administration for the purpose of suppressing or improving allergies.
본 발명의 알레르기 반응 억제용 약제학적 조성물 및 알레르기 반응 억제 및 개선용 건강기능성식품에 포함되는 유효성분인 본 발명의 낙지다리 추출물은 항원 자극에 의한 비만세포의 탈과립, 사이토카인 분비 및 동물모델에서 알레르기 반응을 세포내 Syk/LAT 신호전달경로를 억제함으로써 알레르기 반응 억제 효과가 뛰어나다.The extract of octopus leg of the present invention, which is an effective ingredient contained in the health functional food for inhibiting and alleviating allergic reactions of the present invention and the allergic reaction inhibitory composition of the present invention, can be used as an antiprotozoal agent, The response is suppressed by the intracellular Syk / LAT signaling pathway, thus exerting an allergic reaction inhibitory effect.
알레르기 질환에서 증상 발현에 중요한 역할을 하는 비만세포(mast cell)의 활성의 조절은 알레르기 질환 치료제 개발에서 많은 연구의 대상이 되고 있다. 호염기구와 비만세포에는 알레르기반응을 유도하는 화학매개체들이 포함된 과립들이 세포질 내에 존재한다. 알레르겐이 외부로부터 항원에 의해 자극되어지면 알레르기 반응을 일으키는 물질을 생산, 분비한다(선행문헌 12). 이러한 화학매개체들은 과립안에 이미 생성되어 저장되어있던 물질(preformed mediators)과, 자극 후 새로 생성되는 물질(newly synthesized mediators)로 구성된다. 비만세포 활성화시 분비되는 물질로는 히스타민과 세로토닌이 있으며, 그 외에도 IL-4, IL-13, TNF-α 등의 사이토카인을 분비하여 알레르기성 염증 및 림프구의 증식과 이동을 유도한다(선행문헌 13).The regulation of mast cell activity, which plays an important role in the manifestation of symptoms in allergic diseases, has been the subject of much research in the development of therapeutic agents for allergic diseases. In basophils and mast cells, granules containing chemical mediators that induce allergic reactions are present in the cytoplasm. When an allergen is stimulated by an antigen from the outside, it produces and secretes a substance that causes an allergic reaction (Prior Art 12). These chemical mediators consist of preformed mediators and newly synthesized mediators in the granules. Histamine and serotonin are secreted during mast cell activation and secrete cytokines such as IL-4, IL-13 and TNF-α to induce allergic inflammation and lymphocyte proliferation and migration 13).
이러한 과정은 알레르겐과 비만세포 표면의 고친화성 IgE 수용체(FcεRI)가 결합한 후 신호전달체계가 활성화 되는 Fyn-Gab2-PI3K 경로와 Lyn-Syk-LAT 경로에 따라 진행된다(선행문헌 14). 알레르겐과 FcεRI 간의 집합이 이루어지면 수용체의 β, γ-서브유닛의 ITAM이 Src-키나아제에 의해 인산화되고 Syk 키나아제와 인산화 된 ITAM이 결합하여 Syk의 구조가 변형되면서 신호가 활성화된다. 그 후 하위 신호전달분자 및 어댑터 단백질이 순차적으로 활성되어 비만세포에서 알레르기 유도물질을 분비하고 알레르기 반응을 유도하게 된다(선행문헌 15).This process proceeds according to the Fyn-Gab2-PI3K pathway and the Lyn-Syk-LAT pathway, in which the signaling pathway is activated after binding of allergen and high affinity IgE receptor (FcεRI) on the surface of mast cells (Prior Art 14). When the allergen and FcεRI are assembled, the ITAM of the β, γ-subunit of the receptor is phosphorylated by Src-kinase, and Syk kinase and phosphorylated ITAM bind to each other and Syk's structure is modified to activate the signal. Subsequently, lower signal transduction molecules and adapter proteins are sequentially activated to secrete allergen inducers from mast cells and induce allergic reactions (Prior Art 15).
본 발명의 낙지다리 추출물은 세포독성이 없는 0-100 ㎍/㎖ 농도에서 비만세포 초기 활성신호전달경로인 Syk/LAT의 신호전달경로 활성을 농도 의존적으로 억제함을 확인하였다(도 5).The octopus leg extract of the present invention inhibited the signal transduction pathway activity of the Syk / LAT signaling pathway, which is an initial activity signal of mast cells, at a concentration of 0-100 占 퐂 / ml without cytotoxicity (FIG. 5).
이러한 신호전달을 바탕으로 활성화된 비만세포는 세포질 내 칼슘 농도가 증가되는데 이러한 증가는 비만세포 내의 과립의 탈 과립을 유도한다. 낙지다리 추출물이 비만세포 탈과립 억제의 효과가 있음을 확인하였다(도 1).Based on these signal transduction, activated mast cells increase cytoplasmic calcium concentration, which leads to granule degranulation in mast cells. It was confirmed that octopus leg extract had an effect of inhibiting mast cell degranulation (FIG. 1).
새로운 의약품이 개발될 때 그 물질의 체내 가역성은 매우 중요하다. 일반적으로 비가역적인 물질은 체내 투여시 체내 단백질에 결합하여 그 단백질이 제거 될 때까지 약효를 진속하게 되어 부작용 가능성을 증가 시킨다(선행문헌 16). 이러한 비가역성에 의한 부작용 가능성을 관찰하기 위해 본 발명자는 낙지다리 추출물의 가역성 실험을 진행하였다. 실험 결과 낙지다리 추출물은 비만세포 활성 억제효과가 가역적임을 관찰하였다(도 2). 이러한 가역성은 낙지다리 추출물의 부작용 가능성을 다소 낮추어 준 것으로 평가되었다.When new medicines are developed, their reversibility is very important. In general, irreversible substances bind to proteins in the body when they are administered to the body, and they increase the likelihood of side effects until the proteins are removed (Prior Art 16). In order to observe the possibility of side effects due to such irreversibility, the present inventor carried out a reversibility test of octopus legs extract. As a result of the experiment, it was observed that the octopus legs extract was reversible in inhibiting mast cell activity (FIG. 2). This reversibility was evaluated to lower the possibility of side effects of Octopus legum extract.
최근에 비만세포억제를 통한 알레르기 반응 억제 효능이 있는 식물 추출물에 대한 보고가 다양하게 진행 되어지고 있다. 그 중에서 갈매나무 잎 추출물은 항원 자극에 의한 비만세포의 Fyn 키나아제 활성화 억제를 통해 알레르기 반응을 억제하는 것으로 보고되었다(선행문헌 17). 꾸지뽕나무 추출물은 항원에 의한 비만세포의 Lyn/Syk 경로의 활성화 억제를 통해 알레르기 반응억제 효능을 가지는 것으로 보고되어 갈매나무 추출물의 억제 기전과는 다소 차이가 있음을 알 수 있었다(선행문헌 18). 이러한 식물 추출물의 마우스에서의 알레르기 반응 억제 ED50은 대부분 200-500 mg/kg 이며 본 발명의 낙지다리 추출물의 경우에도 유사한 ED50를 보였다.Recently, there have been various reports on plant extracts having an allergic reaction inhibitory effect through inhibition of mast cells. Among them, Leuconostoc spider leaf extract has been reported to inhibit allergic responses through inhibition of Fyn kinase activation of mast cells by antigenic stimulation (Prior Art 17). It was reported that the extract of Cajrippum japonica has an inhibitory effect on the allergic reaction by inhibiting the activation of the Lyn / Syk pathway of mast cell by the antigen. Allergic reaction inhibition in these plant extracts mouse ED 50 showed a ED 50 is similar to most is 200-500 mg / kg for octopus legs extract of the present invention.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
실험 재료 및 The experimental materials and 실험 동물Experimental animal
DNP(Dinitrophenol)-특이적 IgE와 DNP-우혈청 알부민 항원(DNP-bovine serum albumin, DNP-BSA)는 시그마 알드리치사(St. Louis, MO, USA)에서 구입하였다. 또한 PP2는 칼바이오켐사(La Jolla, CA, USA)에서 구입하였다. RPMI-1640 및 MEM (Minimal Essential Medium) 배지, 배양액에 첨가되는 글루타민과 그 외 세포배양 시약은 GIBCO 테크놀로지 사(Rockville, MD, USA)에서 구입하였다. 웨스턴 블로팅에 사용되는 인산화-Syk 및 인산화-LAT 항체는 셀 시그날링 테크놀로지사 (Danvers, MA, USA)에서 구입하였으며 그 외에 액틴을 검출하기 위한 항체는 밀리포어사 (Billerica, MA, USA)에서 구입하였다. 기타 모든 시약은 시중 제품 중 특급 시약을 구입하여 사용하였다.DNP (Dinitrophenol) -specific IgE and DNP-bovine serum albumin (DNP-BSA) were purchased from Sigma-Aldrich (St. Louis, Mo., USA). PP2 was also purchased from Calbiochem (La Jolla, CA, USA). RPMI-1640 and MEM (Minimal Essential Medium) media, and glutamine and other cell culture reagents added to the culture were purchased from GIBCO Technologies Inc. (Rockville, MD, USA). The phosphorylated-S yk and phosphorylated-LAT antibodies used for Western blotting were purchased from Cellsignaling Technologies (Danvers, MA, USA), and antibodies for detecting actin were purchased from Miller Pore (Billerica, MA, USA) Respectively. All other reagents were purchased and used in the market.
실험에 사용한 동물은, (주)오리엔탈바이오(성남)에서 생후 5 주령 수컷 Balb/c 마우스를 구입하여 사용하였다. 물과 사료는 자유롭게 먹도록 하였으며, 사육환경은 온도 22 ± 1℃, 습도 55 ± 10%로 유지하였고, 낮과 밤의 주기는 각각 12 시간으로 하였다. 모든 실험동물은 1 주일동안 적응시킨 후 실험에 사용하였다. 동물실험은 덕성여자대학교 동물실험윤리 회의 승인을 받아, 동 규정에 따라 실험을 진행하였다.The animals used in the experiment were male Balb / c mice of 5 weeks old at Oriental Biotechnology Co., Ltd. (Seongnam) purchased and used. Water and feed were allowed to eat freely. The breeding environment was maintained at a temperature of 22 ± 1 ° C and a humidity of 55 ± 10%, and the day and night periods were 12 hours each. All experimental animals were adapted for one week and used in the experiment. Animal experiments were approved by the Ethics Committee of Animal Experiment at Duksung Women's University, and the experiment was conducted according to the regulations.
<< 실시예Example 1> 낙지다리 추출물의 제조 1> Preparation of octopus legs extract
본 발명의 실험에 사용한 낙지다리 추출물은 한국식물추출물 은행으로부터 분양(분양번호 007-019) 받아 실험을 진행하였다. 건조된 낙지다리 전초 100 g을 50℃ 메탄올 1000 ml에서 초음파 추출기를 이용하여 추출하였으며 스피드백을 이용하여 40℃에서 24시간 건조과정을 거쳤다. 이러한 과정으로 추출한 낙지다리 추출물의 최종 회수율은 약 15%였다. 비만세포 억제 실험에 사용하기 위해서 DMSO (dimethyl sulfoxide)에 용해시켜 100 mg/ml 농도로 제조한 후, 최종 처리 농도로 희석하여 실험에 적용하였다.The octopus leg extract used in the experiment of the present invention was extracted from the Korean plant extract bank (prevalence No. 007-019) and the experiment was conducted. 100 g of dried octopus legume outpost was extracted with 1000 ml of methanol at 50 ° C using an ultrasonic extractor and dried at 40 ° C for 24 hours using a speed bag. The final recovery rate of the extracted octopus legs was 15%. For use in mast cell inhibition experiments, the cells were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 100 mg / ml and diluted to the final concentration.
<< 실시예Example 2> 낙지다리2> Octopus leg 추출물의 비만세포 Mast cell of extract 탈과립Degranulation (β-(β- hexosaminidasehexosaminidase ) 측정) Measure
IgE 감작된 비만세포는 항원으로부터 자극을 받으면 비만세포 과립 안에 있던 히스타민, β-헥소스아미니다아제, 다양한 프로테아제 등을 세포 밖으로 방출하여 알레르기 반응을 유도한다. 본 실험에서는 탈과립의 지표로서 탈과립에 의해 세포 밖으로 분비된 β-헥소스아미니다아제를 측정하여 낙지다리 추출물의 억제효과를 확인하였다(선행문헌 9).IgE-sensitized mast cells induce allergic reactions by releasing histamine, β-hexosaminidase, various proteases, and the like, which were present in the granules of mast cells, from the cells when stimulated by the antigen. In this experiment, β-hexosaminidase secreted out of cells by degranulation as an indicator of degranulation was measured to confirm the inhibitory effect of octopus legs extract (Prior Art 9).
비만세포로서 RBL-2H3 (Rat Basophil Leukemia)은 ATCC (American Type Culture Collection)에서 분양받아 15% FBS가 포함된 MEM (페니실린 /스트렙토마이신 및 L-glutamine 포함)을 배양액으로 하여 5% CO2 배양기에서, 2-3일 간격으로 계대 배양하였다.As mast cells RBL-2H3 (Rat Basophil Leukemia) is ATCC (American Type Culture Collection) in the pre-sale received 15% FBS containing the MEM (penicillin / streptomycin and L-glutamine included) to the
RBL-2H3 세포를 24-플라스크에 1.8 × 105/웰 농도로 분주하고 20 ng/ml DNP-특이 IgE를 포함한 배지에서 12시간 이상 감작하여 비만세포의 FcεRI를 부위에 IgE가 결합하도록 하였다. 탈과립 정도를 측정하기 위해 β-헥소스아미니다아제(hexosaminidase)의 양을 측정하였다. 측정은 타이로드 완충용액(135 mM NaCl, 5 mM KCl, 20 mM HEPES, 5.6 mM 글루코스, 1.8 mM CaCl2, 1 mM MgCl2, 우혈청으로부터 분리한 지방산 제거된 0.5% 분획, pH 7.4)과 PIPES 완충용액 (25 mM PIPES, 159 mM NaCl, 5 mM KCl, 0.4 mM MgCl2, 1 mM CaCl2, 5.6 mM 글루코스, 우혈청으로부터 분리한 지방산 제거된 0.5% 분획, pH 7.4)을 이용하여 실험을 진행하였다. 우선 37℃ 완충용액으로 각각의 세포를 2번 세척 후 상기 실시예 1에서 제조한 낙지다리 추출물을 웰당 0, 10, 30, 100 ㎍/㎖ 농도로 완충용액에 희석해 첨가하여 30분 동안 전처리를 하였다. 그 후 20 ng/ml의 DNP-특이 IgE 항원을 각 웰에 첨가하여 10분 동안 세포자극을 진행하였다. 10분 배양 후 약 7분간 얼음 위에서 자극을 정지시켰다. 그 후 각 웰의 상층액과 Triton X-100으로 세포를 파쇄하여 얻은 파쇄액을 각각의 96 웰 플레이트에 30 ㎕씩 분주하고 1 mM p-니트로페닐-N-아세틸-β-d-글루코사미나이드를 넣고 1시간 동안 반응시킨 후 250 ul의 0.1 M 카보네이트 완충액을 넣어 반응을 종료한 뒤 405 nm에서 흡광도를 측정하여 정량하였다. 그리고, 대조군으로는 Src-패밀리 키나아제 억제제인 PP2를 10 μM 농도로 처리하였다.RBL-2H3 cells were seeded at a concentration of 1.8 × 10 5 / well in a 24-flask and sensitized with a medium containing 20 ng / ml of DNP-specific IgE for 12 hours or longer to allow IgE to bind to the FcεRI site of mast cells. The amount of? -Hexosaminidase was measured to determine the degree of degranulation. The measurement was carried out using a Tyrode buffer (135 mM NaCl, 5 mM KCl, 20 mM HEPES, 5.6 mM glucose, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 0.5% Experiments were performed using a buffer solution (25 mM PIPES, 159 mM NaCl, 5 mM KCl, 0.4 mM MgCl 2 , 1 mM CaCl 2 , 5.6 mM glucose, 0.5% fraction of fatty acid removed from the serum, pH 7.4) Respectively. First, the cells were washed twice with 37 ° C buffer solution, and then the octopus leg extract prepared in Example 1 was added to the buffer solution at a concentration of 0, 10, 30, 100 μg / ml per well, and pretreated for 30 minutes Respectively. Then 20 ng / ml DNP-specific IgE antigen was added to each well and cell stimulation was performed for 10 minutes. After 10 minutes of incubation, stimulation was stopped on ice for about 7 minutes. Subsequently, the supernatant of each well and the disruption solution obtained by disrupting the cells with Triton X-100 were dispensed into each 96-well plate in an amount of 30 쨉 l, and 1 mM p-nitrophenyl-N-acetyl -? - d-glucosaminate And reacted for 1 hour. Then, 250 μl of 0.1 M carbonate buffer was added to the reaction solution, and the absorbance was measured at 405 nm. As a control group, PP2, an Src-family kinase inhibitor, was treated at a concentration of 10 μM.
그 결과, 항원자극에 의한 비만세포에서의 β-헥소스아미니다아제 분비가 낙지다리 추출물의 처리 농도 의존적으로 억제되었으며, 처리농도 100 ㎍/㎖에서 비만세포의 탈과립 현상이 약 80% 정도가 억제되는 우수한 효능이 관찰되었다(도 1). 이러한 억제효과는 대조군으로서 사용된 Src-패밀리 키나아제 억제제인 PP2의 억제효과와 유사하게 나타났다.As a result, secretion of β-hexosaminidase in mast cell by antigen stimulation was inhibited depending on treatment concentration of octopus legum extract, and about 80% of degranulation phenomenon of mast cell was suppressed at treatment concentration of 100 ㎍ / ㎖ (Fig. 1). This inhibitory effect was similar to the inhibitory effect of PP2, a Src-family kinase inhibitor used as a control.
<< 실시예Example 3> 낙지다리 추출물의 비만세포 3> The mast cell of Octopus legs extract 탈과립Degranulation 억제 효과의 가역성 Reversibility of inhibitory effect
RBL-2H3 세포에 한 그룹은 낙지다리 추출물을 100 ㎍/㎖ 농도로 30분 동안 전처리를 진행하였고 다른 한 그룹은 낙지다리 추출물을 동일한 농도로 30분 전처리한 후 PIPES 완충용액으로 5회 세척하여 탈과립의 현상이 회복되는 것을 관찰하였다.One group of RBL-2H3 cells was pretreated with 100 ㎍ / ㎖ of octopus leg extract for 30 minutes and the other group was pretreated with the same concentration of octopus leg extract for 30 minutes and then washed 5 times with PIPES buffer. The recovery of the phenomenon was observed.
그 결과, 낙지다리 추출물을 100 ㎍/㎖ 농도로 전처리한 군에서 β-헥소스아미니다아제 분비는 대조군과 비교하여 70% 이상 억제되었으나 PIPES 완충용액으로 5회 세척해 준 군은 대조군의 약 90%까지 회복되었다(도 2). 이러한 결과로부터, 낙지다리 추출물의 비만세포 탈과립 억제효과는 가역성을 가짐을 알 수 있었다.As a result, β - hexosaminidase secretion was inhibited by 70% or more in the group pretreated with 100 μg / ml of Octopus legum extract, but in the group of 5 times washed with PIPES buffer, (Fig. 2). From these results, it was found that the inhibitory effect of Octopus legum extract on mast cell degranulation was reversible.
<< 실시예Example 4> 낙지다리 추출물의 비만세포에서 염증성 사이토카인 분비 억제 효과 4> Inhibitory Effect of Octopus Legs Extract on the Secretion of Inflammatory Cytokine from Mast Cells
낙지다리 추출물 전처리에 의한 비만세포에서의 염증성 사이토카인 생산 억제 효과를 RT-PCR 기법으로 측정하였다. 낙지다리 추출물 처리 실험은 상기 실시예 2의 β-헥소스아미니다아제 분비 측정 실험과 동일하게 실시하였으며, 실험 완료후 세포로부터 총 RNA를 분리한 다음 당업계에 알려진 RT-PCR 방법으로 수행하여, 분비된 염증성 사이토카인으로서 TNF-α 와 IL-4의 mRNA 발현 정도를 측정하였다. 단백질의 양을 정량하기 위해 GAPDH의 mRNA 발현으로 정량하였다.The inhibitory effect of octopus legume extract pretreatment on the production of inflammatory cytokines in mast cells was measured by RT-PCR. The octopus leg extract treatment experiment was carried out in the same manner as in the β-hexosaminidase secretion measurement experiment of Example 2, and after completion of the experiment, total RNA was isolated from the cells and then RT- MRNA expression of TNF-α and IL-4 as secreted cytokines was measured. GAPDH mRNA expression was quantitated to quantify the amount of protein.
그 결과, 낙지다리 추출물은 처리 농도 의존적으로 TNF-α 와 IL-4의 mRNA 발현을 현저히 억제하였다(도 3A). IL-4의 mRNA 발현은 낙지다리 추출물의 처리 농도 30 ㎍/㎖ 농도에서부터 대조군과 비교하여 유의적으로 억제되었으며(p < 0.05), TNF-α의 mRNA 발현은 낙지다리 추출물의 처리 농도 100 ㎍/㎖ 농도에서 대조군과 비교하여 유의적으로 억제되었다(p < 0.05), PCE 100 μg/ml에서는 대조약물로 사용된 PP2와 유사한 정도의 억제 효과가 관찰되었다(도 3B).As a result, octopus legum extract significantly inhibited mRNA expression of TNF-a and IL-4 in a concentration-dependent manner (Fig. 3A). IL-4 mRNA expression was significantly (p <0.05) significantly inhibited from the treatment concentration of 30 μg / ㎖ of Octopus legum extracts compared to the control group, and mRNA expression of TNF-α was 100 μg / (P < 0.05) compared to the control group, and a similar inhibitory effect to that of PP2 used as the reference drug was observed at 100 占 퐂 / ml of PCE (Fig. 3B).
<< 실시예Example 5> 낙지다리 추출물의 5> octopus legs extract 세포내Intracellular 칼슘 농도 증가에 따른 Increased calcium concentration 탈과립의Degranulation 억제 효과 Inhibitory effect
낙지다리 추출물의 비만세포 탈과립 억제효과의 기전을 연구하기 위해 우선 이 억제효과가 칼슘이온 증가의 상위 신호전달물질인지 하위 신호경로를 억제하는 것인지를 알아보기 위해 본 실험을 진행하였다.In order to investigate the mechanism of inhibition of mast cell degranulation in octopus legs extract, this experiment was conducted to investigate whether this suppressive effect inhibits the signal transduction pathway or the lower signal pathway of calcium ion increase.
RBL-2H3 세포에 낙지다리 추출물을 웰당 0, 10, 30, 100 ㎍/㎖ 농도로 전처리한 다음, 1 μM 이오노마이신과 300 nM 탭시가긴(thapsigargin)을 처리하였으며, 세포내 칼슘 농도 증가에 따른 탈과립 억제 효과를 확인하기 위해 상기 실시예 2와 동일한 실험을 수행한후 β-헥소스아미니다아제 분비 정도를 확인하였다.RBL-2H3 cells were pretreated with 0, 10, 30, 100 ㎍ / ㎖ per well of octopus legum extract and treated with 1 μM ionomycin and 300 nM thapsigargin. To confirm the degranulation inhibitory effect, the same experiment as in Example 2 was carried out, and the degree of secretion of? -Hexasaminidase was confirmed.
그 결과, 비만세포에 이오노마이신과 탭시가긴을 처리 시 비만세포에서 탈과립이 증가하는 것을 관찰할 수 있었다. 하지만 이러한 물질을 처리하기 전 낙지다리 추출물을 전처리하였을 때 PP2와는 달리 낙지다리 추출물의 전처리에 의해서 탈과립의 억제 효과는 보이지 않았다(도 4). 이러한 결과는 낙지다리 추출물에 의한 비만세포에서의 탈과립 억제효과는 칼슘에 의한 신호전달경로 상위에서 일어나는 것으로 추정되었다.As a result, it was observed that degranulation increased in mast cells when mast cells were treated with ionomycin and tabsigadin. However, unlike PP2, pretreatment of Octopus legum extract did not inhibit degranulation by pretreatment of Octopus legum extract (Fig. 4). These results suggest that the inhibitory effect of octopus legs on the degranulation of mast cells may occur in the upper part of the calcium signal pathway.
<< 실시예Example 6> 낙지다리 추출물의 비만세포에서의 6> Effect of Octopus Leg Extract on Mast Cell SykSyk 및 And LAT의LAT 인산화 억제 효과 Phosphorylation inhibitory effect
낙지다리 추출물의 비만세포에서의 Syk 및 LAT 인산화 억제 효과를 확인하기 위해 비만세포로서 RBL-2H3 및 BMMC 두종류를 사용하였다.Two types of mast cells, RBL-2H3 and BMMC, were used to confirm Syk and LAT phosphorylation inhibitory effects of octopus legum extract on mast cells.
생쥐의 골수에서 유래한 비만세포(BMMCs, Bone marrowderived mast cells)는 5주령의 수컷 Balb/c 마우스의 골수로부터 채취하였다. 마우스로부터 분리한 골수의 세포는 RPMI 배지(RPMI 1640, 10% FBS, 0.1 mM 비-필수 아미노산 및 2 mM L-글루타민 포함)에 IL-3(10 ng/ml)이 포함된 배양액을 사용하여 4주 이상 배양 후 BMMC로의 분화가 98%이상 되었음을 FACS분석을 통해 확인한 후 실험에 사용하였다.Bone marrowderived mast cells (BMMCs) from mouse bone marrow were collected from bone marrow of 5-week-old male Balb / c mice. Bone marrow cells isolated from mice were cultured in RPMI medium (
IgE로 감작된 BMMC 및 RBL-2H3 세포에 PIPES 완충액(또는 타이로드 완충액)으로 희석한 낙지다리 추출물을 웰당 0, 10, 30, 100 ㎍/㎖ 농도로 처리한 다음, 25 ng/ml의 항원(DNP-BSA)을 넣어 7분 동안 자극하고 얼음위에서 반응을 정지시켰다. 항원에 의해 자극된 세포는 약 4℃ PBS 완충용액으로 2번 세척한 후 세포파쇄용액 (20 mM HEPES, pH 7.5, 150 mM NaCl, 1% nonidet P-40, 60 mM octyl β-glucoside, 10% glycerol, 10 mM NaF, 1 mM phenylmethyl-sulfonyl fluoride (PMSF), 1 mM Na3VO4, 2.5 mM nitrophenyl-phosphate, 0.7 mg/ml pepstatin, proteaseinhibior cocktail tablet)으로 10분간 세포를 파쇄 후 15,000rpm, 10분간 4℃에서 원심분리기한 다음 상등액을 얻었다. 이 상등액을 이용하여 단백질 정량 후 100℃에서 3x Laenmmli 완충액으로 약 5분간 끓였다. 정량된 단백질은 SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis)로 분리 후 니트로셀룰로스 멤브레인으로 옮겨 5% BSA를 포함한 TBS-T (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.05% Tween 20) 완충액으로 1시간 동안 블로킹을 시켰다. 이후 분석하고자 하는 단백질(TNF-α, IL-4, 단백질 컨트롤로서 액틴(Actin)에 대한 1차 항체를 1000배로 희석하여 4℃에서 밤새 반응시킨 후 TBS-T로 세척한 뒤 2000배로 희석한 HRP-결합된 2차 항체로 1시간 상온에서 반응시켰다. 이후 10분씩 5번 TBS-T 완충액으로 세척하고 화학발광(chemiluminescence) 분석기로 단백질 밴드를 확인하였다. IgE-sensitized BMMC and RBL-2H3 cells were treated with Pipes buffer (or Tyrod's buffer) diluted octopus leg extract at concentrations of 0, 10, 30, 100 μg / ml per well and then treated with 25 ng / ml of antigen DNP-BSA) was added for 7 min and the reaction was stopped on ice. Cells stimulated by the antigen were washed twice with PBS buffer solution at about 4 ° C and then washed twice with 20 mM HEPES, pH 7.5, 150 mM NaCl, 1% nonidet P-40, 60 mM octyl β-glucoside, The cells were disrupted for 10 min at 15,000 rpm, 10 mM NaCl, 10 mM NaF, 1 mM phenylmethyl-sulfonyl fluoride (PMSF), 1 mM Na 3 VO 4 , 2.5 mM nitrophenyl-phosphate, 0.7 mg / ml pepstatin and proteaseinhibior cocktail tablet) The supernatant was obtained by centrifuging at 4 ° C for a minute. The supernatant was quantitated and the protein was boiled for about 5 minutes at 3O < 0 > C in 3x Laenmli buffer. The purified proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a nitrocellulose membrane. TBS-T (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.05% Tween 20 ) Buffer for 1 hour. Then, the primary antibody against actin (TNF-α, IL-4, and protein) to be analyzed was diluted 1,000-fold and reacted overnight at 4 ° C., washed with TBS-T, The reaction was carried out at room temperature for 1 hour with a conjugated secondary antibody, followed by washing with 5 times TBS-T buffer for 10 minutes, and the protein band was confirmed by a chemiluminescence analyzer.
그 결과, 낙지다리 추출물은 처리 농도 의존적으로 Syk 키나아제의 인산화를 억제하여 활성을 감소시키는 것을 확인할 수 있었다(도 5). 또한, Syk 키나아제의 인산화 활성이 억제됨으로 LAT 인산화 활성역시 감소하는 것을 확인하였다. 따라서 낙지다리 추출물은 Syk 키나아제의 인산화를 억제함으로서 항원에 의해 유도되는 비만세포의 탈과립을 억제할 수 있음을 알 수 있었다. 이러한 결과는 RBL-2H3 세포 뿐만 아니라 골수유래의 세포에서 분화시킨 비만세포(BMMC)에서도 항원 자극에 의한 Syk/LAT 신호전달경로가 유사한 정도로 억제된다는 것을 확인할 수 있었다(도 5).As a result, it was confirmed that octopus leg extract inhibits phosphorylation of Syk kinase by reducing the activity depending on the treatment concentration (FIG. 5). In addition, it was confirmed that the phosphorylation activity of Syk kinase was inhibited and the LAT phosphorylation activity was also decreased. Therefore, it was shown that Octmentus legum extract inhibited the degranulation of mast cells induced by antigen by inhibiting phosphorylation of Syk kinase. These results confirm that the Syk / LAT signaling pathway by antigen stimulation is similarly inhibited in the mast cells (BMMC) differentiated from the bone marrow-derived cells as well as the RBL-2H3 cells (Fig. 5).
<< 실시예Example 7> 낙지다리 추출물의 국소피부자극 알레르기 반응의 억제 효과 7> Inhibitory Effect of Octopus Leg Extract on Local Skin Stimulation Allergy Reaction
알레르기 동물모델에서 낙지다리 추출물의 알레르기 반응 억제효과를 측정하였다. DNP (dinitrophenol)-특이적 IgE에 의한 국소 알레르기 피부 반응(passive cutaneous anaphylaxis, PCA)을 유도하기 위해 마우스(BALB/c, 5주령 수컷)의 오른쪽 귀에 DNP 특이적 IgE를 피내로 0.5 ㎍을 주사하였다. 다음 날 5% 아라비아검 용액에 녹인 낙지다리 추출물을 40 mg/kg, 200 mg/kg 및 1000 mg/kg 농도로 각각 경구 투여하였다. 1 시간 후 항원(DNP-BSA, 1 mg/ml)을 에반스 블루 용액을 이용하여 5 mg/ml 농도로 제조하여 250 ㎕를 꼬리로 정맥 투여하였다. 1 시간 후 마우스를 안락사 시키고 귀를 적출하여 700 ㎕의 포름아마이드로 63℃에서 12 시간 동안 에반스블루를 추출후 상등액을 620 nm의 파장에서 흡광도를 측정하였다. 에반스 블루의 정량은 표준 정량곡선을 이용하여 측정하였다. 낙지다리 추출물의 대조군으로서 세트리진을 20 mg/kg 농도로 동일하게 경구투여하였다.The allergic reaction inhibition effect of octopus legum extract was measured in allergic animal models. To induce a passive cutaneous anaphylaxis (PCA) by DNP (dinitrophenol) -specific IgE, 0.5 μg of DNP-specific IgE was injected intradermally into the right ear of a mouse (BALB / c, 5 week old male) . The next day, the extract of Octopus legum, which was dissolved in 5% gum arabic solution, was orally administered at a concentration of 40 mg / kg, 200 mg / kg and 1000 mg / kg, respectively. After 1 hour, the antigen (DNP-BSA, 1 mg / ml) was prepared at a concentration of 5 mg / ml using Evans Blue solution and 250 μl was intravenously administered by the tail. After 1 hour, the mouse was euthanized, the ear was excised, and Evans blue was extracted with 700 쨉 l of formamide at 63 째 C for 12 hours, and the supernatant was measured for absorbance at a wavelength of 620 nm. Quantitation of Evans Blue was measured using standard quantitative curves. Cetirizine was orally administered at the same concentration of 20 mg / kg as a control group of octopus legs extract.
그 결과, 항원 자극에 의한 알레르기 반응은 잘 유도 되었으며 낙지다리 추출물의 처리에 의해 억제되었다(도 6A). 이러한 억제 결과는 낙지다리 추출물 처리 농도 0-1000 mg/kg 농도 범위 내에서 농도 의존적으로 억제되었으며 최고농도인 1000 mg/kg 투여군에서는 대조약물로 사용된 세트리진과 동일한 효과를 보였다.As a result, the allergic reaction by the antigen stimulation was well induced and was inhibited by treatment of Octopus legum extract (Fig. 6A). These inhibition results were inhibited in a concentration-dependent manner within a concentration range of 0-1000 mg / kg of octopus leg extract treatment, and the same effect was observed with the highest dose of 1000 mg / kg in the group treated with sertoliene.
Claims (9)
A pharmaceutical composition for preventing, ameliorating or treating an allergic disease containing an extract of Octopus chinense Pursh as an active ingredient.
The method according to claim 1, wherein the octopus legs extract is selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol and butanol, ethyl acetate, acetone, ether, benzene, chloroform, methylene chloride, hexane, Hexane and water. ≪ RTI ID = 0.0 > 8. < / RTI >
3. The pharmaceutical composition according to claim 2, wherein the octopus leg extract is extracted using methanol as an extraction solvent.
상기 단계의 추출 여액을 여과한 후 건조하여 농축하는 단계를 통해 제조되는 것을 특징으로 하는 약제학적 조성물.
[3] The method according to claim 1, wherein the octopus legs extract is extracted with an ultrasonic extractor by adding a methanol solvent to the octopus legs outpost;
And filtering the extracted filtrate, drying and concentrating the extracted filtrate.
The pharmaceutical composition according to claim 1, wherein the octopus leg extract is contained in the composition at a concentration of 10 to 1000 mg / μl.
The pharmaceutical composition according to claim 1, wherein the octopus leg extract is administered at a concentration of 10 to 1000 mg / kg when administered to a human body.
The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition can prevent or treat at least one disease selected from the group consisting of asthma, allergic rhinitis, atopy, and chronic obstructive pulmonary disease caused by allergy ≪ / RTI >
A health functional food for improving the allergic reaction containing the extract of Octmentus chinense (Pursh) as an active ingredient.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101534616B1 (en) | 2013-11-22 | 2015-07-09 | 충남대학교산학협력단 | Composition for Anti-Influenza Virus Comprising Penthorum chinense Pursh Extract |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190040895A (en) * | 2017-10-11 | 2019-04-19 | 재단법인 경기도경제과학진흥원 | Method For Preparing Penchinone A And Its Derivatives And Anti-inflammatory Use Thereof |
| KR20190040867A (en) * | 2017-10-11 | 2019-04-19 | 재단법인 경기도경제과학진흥원 | Method For Preparing Penchinone A or Its Derivatives And Anti-inflammatory Composition Using the Same |
| KR102051431B1 (en) | 2017-10-11 | 2019-12-04 | 재단법인 경기도경제과학진흥원 | Method For Preparing Penchinone A or Its Derivatives And Anti-inflammatory Composition Using the Same |
| KR102084982B1 (en) | 2017-10-11 | 2020-03-05 | 재단법인 경기도경제과학진흥원 | Method For Preparing Penchinone A And Its Derivatives And Anti-inflammatory Use Thereof |
| KR102406286B1 (en) | 2021-12-23 | 2022-06-13 | 국립낙동강생물자원관 | Antibacterial composition using extract of Penthorum chinense |
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